The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma

The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter ( TERTp ) and isocitrate dehydrogenase 1 or 2 ( IDH ). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX- mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, about 20% of glioblastomas lack alterations in TERTp and IDH . These tumors, designated TERTp WT - IDH WT glioblastomas, do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we report the genetic landscape of TERTp WT - IDH WT glioblastoma and identify SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT. Furthermore, we identify a novel mechanism of telomerase activation in glioblastomas that occurs via chromosomal rearrangements upstream of TERT . Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT -structural rearrangements ( IDH WT - TERT SV ), and an ALT-positive subgroup ( IDH WT -ALT) with mutations in ATRX or SMARCAL1 .